Bone marrow transplantation (BMT) is the treatment of choice for many inherited diseases including severe immunodeficiency disease (SCID), thalassemia, and Hurler's mucopolysaccharidosis. Limitations to using BMT include 1) toxic chemotherapy necessary to prevent graft rejection; 2) risk of T lymphocyte mediated graft-vs-host-disease (GVHD); and 3) limited number (25%) of patients with an HLA matched donor. Early in gestation, the fetus cannot reject transplanted marrow, and techniques are available for T cell depleting (TCD) mismatched parental marrow eliminating GVHD. Our hypothesis is that inherited diseases which can be diagnosed early in gestation can be safely cured with an in utero bmt without needing chemotherapy. The fetal rhesus model is essential to testing this hypothesis and developing innovative techniques for enhancing tolerance induction. In the 1993-94 season we transplanted 8 fetuses at gestational ages 43-49 days. The recipients were sexed by pcr analysis of chorionic villous samples, and the donor was of the opposite sex. Our first experiment tested the hypothesis that multiple in utero boosts of tcd parental marrow would increase the percent of donor cells postnatally. We compared in 3 different recipients, a single boost, 3 boosts and 7 boosts of donor cells prior to birth; the results of this experiment are pending. The second experiment evaluated whether tcd human cord blood stem cells could engraft in the fetal rhesus monkey. We are able to identify human donor cells in fetal liver, spleen, blood and marrow one month post transplant and in bone marrow 10 months postnatally in 3 of 5 animals that received transplant. We are now doing experiments to determine the lineages that have engrafted and the extent of tolerance induction. We are also evaluating different sources of stem cells including late gestation fetal liver and recruited peripheral blood stem cells.